To cite this version:P. Foy, Chloé Bertolus, Marie-Cécile Michallet, Sophie Deneuve, R. Incitti, et al.. The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade. Annals of Oncology, Oxford University Press (OUP), 2017, 28 (8), pp.1934-1941 Background: Never-smokers and never-drinkers patients (NSND) suffering from oral

DNA promoter methylation of tumor suppressor genes and global DNA hypomethylation are common features of head and neck cancers. Our goal was to identify early DNA methylation changes in oral premalignant lesions (OPLs) that may serve as predictive markers of developing oral squamous cell carcinoma (OSCC). Using high-throughput DNA methylation profiles of 24 OPLs, we found that the top 86 genes differentially methylated between patients who did or did not develop OSCC were simultaneously hypermethylated, suggesting that a CpG island methylation phenotype may occur early during OSCC development. The vast majority of the 86 genes were non-methylated in normal tissues and hypermethylated in OSCC versus normal mucosa. We used pyrosequencing in a validation cohort of 44 patients to evaluate the degree of methylation of AGTR1, FOXI2, and PENK promoters CpG sites that were included in the top 86 genes, and of LINE1 repetitive element methylation, a surrogate of global DNA methylation. A Methylation Index (MI) was developed by averaging the percent methylation of AGTR1, FOXI2, and PENK promoters; patients with a high MI had a worse OCFS (P=0.0030). On the other hand, patients with low levels of LINE1 methylation had a significantly worse OCFS (P=0.0153). In conclusion, AGTR1, FOXI2 and PENK promoter methylation and LINE1 hypomethylation may be associated with an increased risk of OSCC development in patients with OPLs.

Introduction: An increasing number of parameters can be considered when making decisions in oncology. Tumor characteristics can also be extracted from imaging through the use of radiomics and add to this wealth of clinical data. Machine learning can encompass these parameters and thus enhance clinical decision as well as radiotherapy workflow. Methods: We performed a description of machine learning applications at each step of treatment by radiotherapy in head and neck cancers. We then performed a systematic review on radiomics and machine learning outcome prediction models in head and neck cancers. Results: Machine Learning has several promising applications in treatment planning with automatic organ at risk delineation improvements and adaptative radiotherapy workflow automation. It may also provide new approaches for Normal Tissue Complication Probability models. Radiomics may provide additional data on tumors for improved machine learning powered predictive models, not only on survival, but also on risk of distant metastasis, in field recurrence, HPV status and extra nodal spread. However, most studies provide preliminary data requiring further validation. Conclusion: Promising perspectives arise from machine learning applications and radiomics based models, yet further data are necessary for their implementation in daily care.

This case series study evaluates head and neck injuries caused by electric scooters in Paris, 2017-2019, focusing on user behavior and injury types.

Oral squamous cell carcinoma (OSCC) is a major cause of cancer-associated morbidity and mortality and may develop from oral premalignant lesions (OPL). An improved molecular classification of OPL may help refining prevention strategies. We identified two main OPL gene-expression subtypes, named immunological and classical, in 86 OPL (discovery dataset). A gene expression-based score was then developed to classify OPL samples from three independent datasets, including 17 (GSE30784),13 (GSE10174) and 15 (GSE85195) OPLs, into either one of the two gene-expression subtypes. Using the single sample gene set enrichment analysis, enrichment scores for immune-related pathways were different between the two OPL subtypes. In OPL from the discovery set, loss of heterozygosities (LOH) at 3p14, 17p13, TP53, 9p21 and 8p22 and miRNA gene expression profiles were analyzed. Deconvolution of the immune infiltrate was performed using the Microenvironment Cell Populations-counter tool. A multivariate analysis revealed that decreased miRNA-142-5p expression (P = 0.0484) and lower T-cell, monocytic and myeloid dendritic cells (MDC) immune infiltration (T-cells, P = 0.0196; CD8 T cells, P = 0.0129; MDC, P = 0.0481; and monocytes, P = 0.0212) were associated with oral cancer development in the immunological subtype only. In contrast, LOH at 3p14 (P = 0.0241), 17p13 (P = 0.0348) and TP53 (P = 0.004) were associated with oral cancer development in the classical subtype only. In conclusion, we identified 2 subtypes of OPLs, namely immune and classical, which may benefit from different and specific personalized prevention interventions.

At the time of diagnosis, 60% of patients with head and neck squamous cell carcinoma (HNSCC) present tumors in an advanced stage (III-IV) of disease and 80% will relapse within the first two years post-treatment, due to their frequent radio(chemo)resistance. To identify new molecular targets and companion biomarkers, we have investigated the miRNome of 75 stage III-IV oropharynx tumors without relapse (R) or with loco-regional relapse (non-responder, NR) within two years post-treatment. Interestingly, miR-422a was significantly downregulated in NR tumors, in agreement with the increase in cell proliferation and adhesion induced by miR-422a inhibition in vitro. Furthermore, we identified CD73/NT5E oncogene as target of miR-422a. Indeed, modulation of the endogenous level of miR-422a inversely influences the expression and the enzymatic activity of CD73. Moreover, knocking down CD73 mimics the effects of miR-422a upregulation. Importantly, in tumors, miR-422a and CD73 expression levels are inversely correlated, and both are predictive of relapse free survival - especially considering loco(regional) recurrence - in vitro two independent cohorts of advanced oropharynx or HNSCC (N=255) tumors. In all, we reported, for the first time, that MiR-422a and its target CD73 are involved in early loco(regional) recurrence of HNSCC tumors and are new targets for personalized medicine.

Objective: To summarize the results of pelvic insufficiency fracture (PIF) incidence in patients with anal or gynaecological cancer treated by pelvic intensitymodulated radiation therapy (IMRT). Methods: The clinical and morphological (CT and/or pelvic MRI) characteristics of patients treated by IMRT at our institution between 2007 and 2014 were analyzed. The global incidence of PIF after external beam radiotherapy and the impact of tumour site (gynaecological or anal cancer) were determined. A dosimetric study was then performed to compare patients with and without pelvic fracture. Results: 341 patients were treated by IMRT for gynaecological or anal cancer between 2007 and 2014. 15 patients experienced at least 1 pelvic fracture after external beam radiotherapy, corresponding to an overall incidence of 4.4%. Age and menopausal status were correlated with an increased fracture risk (p 5 0.0274 and p , 0.0001, respectively). The site of the primary tumour (gynaecological or anal canal) was not associated with an excess fracture risk. The median maximum dose received at the fracture site was 50.3 Gy (range: 40.8-68.4 Gy). Conclusion: The incidence of pelvic fracture after IMRT is low, but is higher after the age of 50 and in patients who are postmenopausal. Pre-treatment evaluation of bone density by bone densitometry and phosphorus-calcium assessment could be useful prior to the management of these patients. Advances in knowledge: Pelvic fractures are a frequent complication after radiotherapy. The influence of IMRT and clinical characteristics were evaluated in this study.

BackgroundRadiotherapy for head and neck squamous cell carcinomas (HNSCC) is associated with a substantial morbidity and inconsistent efficacy. Human papillomavirus (HPV)-positive status is recognized as a marker of increased radiosensitivity. Our goal was to identify molecular markers associated with benefit to radiotherapy in patients with HPV-negative disease.MethodsGene expression profiles from public repositories were downloaded for data mining. Training sets included 421 HPV-negative HNSCC tumors from The Cancer Genome Atlas (TCGA) and 32 HNSCC cell lines with available radiosensitivity data (GSE79368). A radioresistance (RadR) score was computed using the single sample Gene Set Enrichment Analysis tool. The validation sets included two panels of cell lines (NCI-60 and GSE21644) and HPV-negative HNSCC tumor datasets, including 44 (GSE6631), 82 (GSE39366), and 179 (GSE65858) patients, respectively. We finally performed an integrated analysis of the RadR score with known recurrent genomic alterations in HNSCC, patterns of protein expression, biological hallmarks, and patterns of drug sensitivity using TCGA and the E-MTAB-3610 dataset (659 pancancer cell lines, 140 drugs).ResultsWe identified 13 genes differentially expressed between tumor and normal head and neck mucosa that were associated with radioresistance in vitro and in patients. The 13-gene expression-based RadR score was associated with recurrence in patients treated with surgery and adjuvant radiotherapy but not with surgery alone. It was significantly different among different molecular subtypes of HPV-negative HNSCC and was significantly lower in the “atypical” molecular subtype. An integrated analysis of RadR score with genomic alterations, protein expression, biological hallmarks and patterns of drug sensitivity showed a significant association with CCND1 amplification, fibronectin expression, seven hallmarks (including epithelial-to-mesenchymal transition and unfolded protein response), and increased sensitivity to elesclomol, an HSP90 inhibitor.ConclusionsOur study highlights the clinical relevance of the molecular classification of HNSCC and the RadR score to refine radiation strategies in HPV-negative disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0929-y) contains supplementary material, which is available to authorized users.